Fatty acid amide hydrolase (FAAH) serves as the catabolic regulator of several endogenous lipid amides including anandamide (1a) and oleamide (1b), below. Its distribution is consistent with its role in hydrolyzing and regulating such signaling fatty acid amides at their sites of action. Although it is a member of the amidase signature family of serine hydrolases for which there are a number of prokaryotic enzymes, it is the only well characterized mammalian enzyme bearing the family's unusual Ser-Ser-Lys catalytic triad.
Substrates of Fatty Acid Amide Hydrolase (FAAH):

Due to the therapeutic potential of inhibiting FAAH for the treatment of pain inflammation, or sleep disorders, for example, there has been growing interest in the development of selective inhibitors of the enzyme. Early studies following the initial characterization of the enzyme led to the discovery that the endogenous sleep-inducing molecule 2-octyl α-bromoacetoacetate is an effective FAAH inhibitor, and the disclosure of a series of nonselective reversible inhibitors bearing an electrophilic ketone. Subsequent studies have defined two major classes of inhibitors that provide opportunities for the development of inhibitors with greater therapeutic potential. One class is the reactive aryl carbamates and ureas that irreversibly acylate a FAAH active site serine and that have been shown to exhibit anxiolytic activity and produce antinociceptive effects. A second class is the α-ketoheterocycle-based inhibitors that bind to FAAH by reversible hemiketal formation with an active site serine.
Compound 2 (OL-135), which is disclosed and claimed in U.S. Pat. No. 7,662,971 by certain of the inventors herein,
is a FAAH inhibitor that induces analgesia and increases endogenous anandamide levels. It exhibits antinociceptive and anti-inflammatory activity in a range of preclinical animal models that include the tail flick assay, hot plate assay, formalin test of noxious chemical pain (1st and 2nd phase), the mild thermal injury (MTI) model of peripheral pain, the spinal nerve ligation (SNL) and chronic constriction injury (CCI) models of neuropathic pain, and an inflammatory model of pruritus with good efficacy.
There is a need, however, for improved antinocioceptive compounds that is believed can be filled by FAAH inhibitors having appropriate characteristics.